chr19-40800316-C-CTT

Variant names:

• chr19-40800316-C-CTT
• rs35057638
• ENST00000593726.5:c.-247_-246dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000593726.5(EGLN2):​c.-247_-246dupTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 250,710 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: EGLN2 ENST00000593726.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.329
• Publications: 2 publications found

Genes affected

EGLN2 (HGNC:14660): (egl-9 family hypoxia inducible factor 2) The hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degration by prolyl hydroxylation. This gene encodes an enzyme responsible for this post-translational modification. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream RAB4B (RAB4B, member RAS oncogene family) gene. [provided by RefSeq, Feb 2011]

RAB4B-EGLN2 (HGNC:44465): (RAB4B-EGLN2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RAB4B (RAB4B, member RAS oncogene family) and EGLN2 (egl nine homolog 2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000593726.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	NM_080732.4	MANE Select	c.-234-13_-234-12dupTT		intron	N/A	NP_542770.2	Q96KS0-1
	EGLN2	NM_053046.4		c.-234-13_-234-12dupTT		intron	N/A	NP_444274.1	Q96KS0-1
	RAB4B-EGLN2	NR_037791.1		n.815-13_815-12dupTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	ENST00000593726.5	TSL:1	c.-247_-246dupTT		5_prime_UTR	Exon 1 of 5	ENSP00000469686.1	Q96KS0-1
	EGLN2	ENST00000303961.9	TSL:1 MANE Select	c.-234-13_-234-12dupTT		intron	N/A	ENSP00000307080.3	Q96KS0-1
	EGLN2	ENST00000406058.6	TSL:1	c.-234-13_-234-12dupTT		intron	N/A	ENSP00000385253.1	Q96KS0-1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.000144 AC: 36 AN: 250710 Hom.: 0 Cov.: 0 AF XY: 0.000155 AC XY: 20 AN XY: 129406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000121 AC: 1 AN: 8242

American (AMR) AF: 0.0000997 AC: 1 AN: 10032

Ashkenazi Jewish (ASJ) AF: 0.000122 AC: 1 AN: 8190

East Asian (EAS) AF: 0.000255 AC: 5 AN: 19620

South Asian (SAS) AF: 0.000120 AC: 2 AN: 16720

European-Finnish (FIN) AF: 0.0000605 AC: 1 AN: 16542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1132

European-Non Finnish (NFE) AF: 0.000148 AC: 23 AN: 155118

Other (OTH) AF: 0.000132 AC: 2 AN: 15114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 69

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35057638; hg19: chr19-41306221;